Fertility care among people with primary ciliary dyskinesia
1Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
2Graduate School for Health Sciences, University of Bern, Bern, Switzerland
3Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, University Hospital, University of Bern, Bern, Switzerland
4PCD Support UK, London, United Kingdom
5PCD Foundation, Minneapolis, USA
6Sorbonne University, INSERM UMR 933, 75012 Paris, France
7Univ Paris Est-Créteil, Faculté de Santé, INSERM, IMRB, Créteil, France
8Pulmonary Department, Centre Hospitalier Intercommunal de Créteil, France
*Corresponding author: Eva Sophie Lunde Pedersen, Institute of Social and Preventive Medicine, University of Bern, Switzerland. Mittelstrasse 43, 3012 Bern, Switzerland, Email: eva.pedersen@unibe.ch, Tel: +41 684 56 75Abstract
Introduction
Fertility care is important for people living with primary ciliary dyskinesia (PCD) who are at increased risk of fertility problems. We investigated fertility care in an international participatory study.
Methods
Participants of the COVID-PCD study completed an online questionnaire addressing fertility issues. We used logistic regression to study factors associated with fertility specialist visits.
Results
Among 384 respondents (response rate 53%), 266 were adults [median age 44 years, interquartile range (IQR) 33–54), 68% female], 16 adolescents, and 102 parents of children with PCD. Half adult participants (128; 48%) received care from fertility specialists at a median age of 30 years (IQR 27–33)—a median of 10 years after PCD diagnosis. Fertility specialist visits were reported more often by adults with pregnancy attempts [odds ratio (OR) 9.1, 95% confidence interval (CI) 3.8–23.6] and among people who reported fertility as important for them (OR 5.9, 95% CI 2.6–14.6) and less often by females (OR 0.4, 95% CI 0.2–0.8). Only 56% of participants who talked with healthcare professionals about fertility were satisfied with information they received. They expressed needs for more comprehensive fertility information and reported dissatisfaction with physician knowledge about PCD and fertility.
Conclusion
People with PCD are inconsistently referred to fertility specialists. We recommend care from fertility specialists become standard in routine PCD care, and that PCD physicians provide initial fertility information either at diagnosis or no later than transition to adult care.
Article notes
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
Our research was funded by the Swiss National Science Foundation, Switzerland (SNSF 320030B_192804/1), the Swiss Lung Association, Switzerland (2021-08_Pedersen), and we also received support from the PCD Foundation, United States; the Verein Kartagener Syndrom und Primaere Ciliaere Dyskinesie, Germany; the PCD Support UK; and PCD Australia, Australia. M. Goutaki receives funding from the Swiss National Science Foundation (PZ00P3_185923). Study authors participate in the BEAT-PCD Clinical Research Collaboration supported by the European Respiratory Society.
Introduction
Fertility care is important for people living with primary ciliary dyskinesia (PCD) who are at increased risk of fertility problems. PCD is a rare genetic disease which affects the function and structure of motile cilia. Motile cilia are found in the respiratory tract, fallopian tubes, and efferent ductules 1, 2. In addition, sperm flagella share common structures with motile cilia 3. In females, it was hypothesized the abnormal motion of cilia in fallopian tubes possibly leads to infertility and more ectopic pregnancies 1, 4, 5. Male infertility is likely caused by reduced sperm count in ejaculate from altered motility of cilia in the efferent ductules or by dysmotile sperm 2, 3, 6. However, the extent of fertility problems—especially among females—is unknown 7.
Fertility care is defined as interventions that include fertility awareness, support and fertility management 8. Patients with PCD would benefit from fertility care as it provides information for making informed decisions about reproductive health. If needed, assisted reproduction interventions, such as in vitro fertilization with or without intracytoplasmic sperm injections, could be offered early on to increase chances of pregnancy. However, no clear guidelines currently exist for integrating fertility care into routine PCD care. Recommendations about fertility care are scarce and imprecise 9–15. It is unclear how fertility care is implemented into routine PCD care, what information is provided and when, and whether people with PCD are satisfied with fertility information they receive. For cystic fibrosis (CF)—another rare genetic lung disease—fertility issues are also present among most males and some females. Studies about CF and reproductive health suggest adults, adolescents, and parents of children with CF know about the possibility of fertility problems, yet lack important CF-specific reproductive health information 16–20. CF and reproductive health studies share clear recommendations for standardized education about reproductive health 16, 21.
Using data from the largest study worldwide collecting information directly from people with PCD (COVID-PCD), we studied fertility care among people with PCD, including their sources of and factors for referrals to fertility specialists and satisfaction with fertility information received.
Methods
Study design and ethics
We obtained study data from a cross-sectional questionnaire about fertility nested within the COVID-PCD study. COVID-PCD is an international participatory cohort study that collects information directly from people with PCD (clinicaltrials.gov: NCT04602481). A detailed study protocol has been published 22. In brief, the COVID-PCD study was set up in 2020 at the University of Bern, Switzerland in collaboration with international PCD patient support groups to follow people with PCD through the pandemic and answer other PCD-related research questions. The COVID-PCD study enrolls participants of any age with PCD from all over the world with suspected or confirmed PCD diagnoses. The study is online, anonymous, and longitudinal. Questionnaires are available in five languages (English, French, German, Italian, and Spanish).
The cantonal ethics committee of Bern approved the study (study ID: 2020-00830). We obtained informed consent either from participants or parents of participants younger than age 14. We report according to strengthening the reporting of observational studies in epidemiology (STROBE) recommendations 23.
Study procedures
Participants registered via the study website (www.covid19pcd.ispm.ch) and received a baseline questionnaire, then weekly follow-up questionnaires. We sent a fertility questionnaire by email on July 12, 2022 to all participants enrolled in the COVID-PCD study. We sent up to three reminders if participants did not yet complete the questionnaire. We collected responses until March 8, 2023. All data was entered directly in a web-based database using the Research Electronic Data Capture (REDCap) platform 24 hosted by the Swiss medical registries and data linkage center (SwissRDL) at the University of Bern.
Fertility questionnaire
We developed the fertility questionnaire based on existing literature, and we discussed it with fertility specialists and patient representatives from PCD support groups. We include questions and answer categories in Supplementary Table S1. We developed separate questionnaires for adults older than 18 years, adolescents ages 14–17 years, and parents of children with PCD younger than 14 years. Native speaking members from patient support groups or our research team translated questionnaires; two research team members independently checked translations.
Information on fertility care characteristics
In the adult questionnaire, we asked participants if ever referred to fertility specialists; if so, at what age and who provided referrals. We calculated time until fertility specialist visit as the difference between age at PCD diagnosis (or age 18 for people diagnosed during childhood) and age at fertility specialist visit. We excluded adults who were diagnosed with PCD only after fertility specialist visits or with unreported ages at PCD diagnosis or at fertility specialist visit.
We asked all participants (adults, adolescents, and parents) their opinions about the need for fertility care, their fertility information seeking behaviors, and sources of fertility information they used. Among participants who previously talked with healthcare professional about fertility, we asked about what topics were discussed and whether they were satisfied with fertility information they received. We asked participants who reported they were either partly satisfied or unsatisfied with provided fertility information to pinpoint information gaps.
We studied how fertility care from fertility specialists differed by age and country. For adults, age at survey, age at diagnosis, and age at fertility specialist visit were categorized as either 18–30 years, 31–45 years, or older than 45 years. We chose age groups according to physiological female fertility changes with peak reproductive years between late teens and late 20s; declining fertility starting by age 30 and by age 45, fertility declining so much pregnancy without medical assistance is unlikely for most females 25. For simplicity, we used the same age groups for males. We categorized country of residence. We combined Canada and the United States as North America because their PCD care is organized in a network. We included England, Northern Ireland, Scotland, and Wales as the United Kingdom. We grouped countries with fewer than 25 participants into either “other European countries” or “other non-European countries” (Supplementary Table S2).
Data analysis
We described fertility care separately for females and males. We compared time from diagnosis (or age 18 for people diagnosed during childhood) until fertility specialist visit between females and males using Mann Whitney U test. We studied factors associated with fertility specialist visits using multivariable logistic regression with sex, age at survey, age at PCD diagnosis, pregnancy attempt, and self- assessed importance of fertility as explanatory variables. For the regression analysis, we excluded people with missing values for age at PCD diagnosis and without information on pregnancy attempts. Each variable had <5% missing data. We used R version 4.2.0 for all analyses 26.
Results
Study population
In total, 384 of 723 COVID-PCD participants (response rate 53%) completed the fertility questionnaire (Supplementary Table S3). Of these, 266 were adults (69%) with a median age of 44 years [interquartile range (IQR) 33–54]; 16 adolescents (4%), and 102 parents of children with PCD (27%). Two-thirds of adult participants were female (181; 68%). Most participants were from North America (71; 18%), the United Kingdom (66; 17%), and Germany (62; 16%). Compared with non- participants, people who completed the fertility questionnaire were older and more often living in Germany, Switzerland, Australia, and other European countries (Supplementary Table S3).
Fertility care among adults
Half of adult participants (128; 48%) reported receiving fertility care from fertility specialists before completing the survey (Table 1) with a higher proportion of males (47; 55%) than females (81; 45%). The median age at fertility specialist visit was 30 years (IQR 27–33). Only 15 (12%) participants were referred by their PCD physicians, while most participants either reported referrals by non-PCD physicians (46; 36%) or organized appointments themselves (43; 34%) (Table 1). The median time between PCD diagnosis (or age 18 for people diagnosed during childhood) and fertility specialist visit was 10 years, and higher among females (11 years, IQR 7–13) than males (7.5 years, IQR 0–14) (p-value 0.06).
Adults who received fertility care from fertility specialists were less often female [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2–0.8], more often reported prior pregnancy attempts (OR 9.1, 95% CI 3.8–23.6) and fertility as an important issue (OR 5.9, 95% CI 2.6–14.6) (Table 2). The proportion of people who reported fertility care from fertility specialists differed between countries with the highest in France (11; 69%) and lowest in Italy (7; 35%).
Most participants (370; 96%) felt people with PCD should be referred for fertility care by fertility specialists (Table 3), yet opinions about the timing of fertility care differed. More than one-third (144; 38%) reported everyone should be referred; many (102; 27%) thought only people who want children should be referred; some (78; 20%) felt only adults and few (37; 10%) reported only people with unsuccessful pregnancy attempts should be referred.
Fertility information among all participants
Most participants (277; 72%) searched for information about fertility (Table 3). They mostly searched multidisciplinary PCD network websites (119; 43%) or scientific articles (92; 33%). Around half (203; 53%) of all participants talked about fertility with healthcare professionals involved in their PCD care prior to the study, with adult females (108; 60%) and adult males (61; 72%) more often than parents of children (32; 31%) and adolescents (2; 13%) with PCD (Table 3). Participants reported most healthcare professionals mentioned people with PCD may have problems with fertility (females: 97; 90%, males: 53; 87%, parents: 30; 94%) (Figure 1). More than half of adult participants received information about the possibility of fertility treatments (females: 67; 62%, males: 33; 54%) and one-quarter (females: 31; 29%, males: 16; 26%) were informed about fertility awareness factors other than PCD influencing fertility, such as advanced age or lifestyle factors. Overall, half of participants (111; 56%) were satisfied with information from healthcare professionals, ranging from fewer than half of females (49; 45%) to three-quarters of males (43; 72%) (Figure 2). Participants who reported dissatisfaction with fertility information noted information gaps, such as detailed information about effects from PCD on fertility (18; 20%), effects on female fertility specifically (8; 9%) or information and advice on fertility treatments (9; 10%). They reported dissatisfaction with physician knowledge about PCD and fertility (16; 18%). Eight participants reported fertility was not yet relevant because the person diagnosed with PCD was young; and five reported long ago PCD-fertility discussions with little known about PCD at the time of the conversation (Table 4).
Discussion Summary of findings
In the first study on fertility care among people with PCD, we showed only 48% of adults with PCD reported ever visiting fertility specialists with a median delay of 10 years since diagnosis (or age 18 for people diagnosed during childhood). Only 12% were referred to fertility specialists by their PCD physician. Among participants with PCD who spoke with healthcare professional about fertility, only 56% reported satisfaction with provided information. They expressed needs for more comprehensive fertility information, such as detailed information about effects from PCD on fertility.
Strengths and weaknesses
Using data from the largest study with patient-reported data in PCD, we collected information about fertility care and opinions from people with PCD. Above all, our results represent relevance for people with PCD. Since we conducted our study online and anonymously, we involved people normally with limited involvement in research from many countries around the world.
Our study also has limitations. People who talked with healthcare professionals about fertility long ago possibly found it difficult to recall conversation details, which could lead to recall bias. However, we did not ask detailed questions about fertility discussions; instead, we focused on general aspects and opinions. Therefore, we expected respondents to remember the main points discussed. Fertility is a sensitive topic and people with negative fertility care experiences possibly participate more as an opportunity to make themselves heard, which could lead to selection bias.
Comparison with other studies
To our knowledge, no other study investigated fertility care among people with PCD. Review papers on managing PCD suggest including fertility topics in routine PCD care 10, 15. The PCD Foundation recommends including reproductive medicine “as clinically needed” 9; Werner et al. note “infertility is managed with adequate reproductive techniques” 14; and Lucas et al. suggest integrating fertility care at transition into adult care 13. For male infertility, two reviews promote including fertility care during the transition from pediatric to adult care 27 3. However, none explicitly counsel how and when fertility care should be included; how it should be organized; and what topics should be addressed 7. In CF research, recent reproductive health reviews address some of these questions and propose management strategies for healthcare professionals 21, 28–31. However, data on fertility care implementation show reproductive health needs are not proactively addressed among people with CF 32. Adults and adolescents with CF report inadequate communication on the topic from CF care providers 17, 18 and delayed introduction of reproductive health education 16. Only 30% of parents of children with CF were satisfied with their current knowledge of reproductive health 20. Results from our study confirm people with PCD face similar challenges in terms of fertility care and highlight important gaps in PCD care and existing recommendations.
Interpretation of results
Young adults with PCD are not referred to fertility specialists as part of routine PCD care. Most seem only to be referred when experiencing fertility problems, and usually at their own request. Females are referred later than males, although an early visit would be even more important for them since their fertility declines earlier. This suggests fertility care is not satisfactorily integrated in routine PCD care and potential fertility problems are not proactively addressed before becoming relevant to people with PCD. Only one-quarter of participants were informed by healthcare professionals about other fertility awareness factors, such as age, influencing fertility; only half of participants were informed about the possibility of fertility treatments. Our results also suggest great dissatisfaction among people with PCD regarding their fertility care. Most participants expressed a need for more comprehensive information about fertility for people with PCD. This also reflects the general lack of knowledge regarding fertility issues among people with PCD—especially in females—and indicates a need for further research. Until this knowledge gap is filled, fertility care will have limitations.
PCD physicians may not recognize the need to address fertility as it is out of their area of expertise. Nevertheless, it is likely beneficial for PCD physicians to openly discuss potential fertility issues. Already at diagnosis, PCD physicians can provide information about potential impact from PCD on fertility and—no later than the transition to adult care—offer information about fertility awareness, such as age or timing of sexual intercourse. By integrating fertility care, physicians could mention ways to increase chances of pregnancy through fertility treatments and interventions, offer further fertility information, and organize referrals to fertility specialists if needed.
Conclusion
People with PCD are inconsistently referred to fertility specialists and report difficulties obtaining satisfactory fertility information. We recommend care from fertility specialists become standard in routine PCD care, and PCD physicians provide initial fertility information either at diagnosis or no later than transition to adult care.
Data Availability
All data produced in the present study are available upon reasonable request to the authors
Acknowledgments
We thank all participants and their families, and we thank the PCD support groups and physicians who advertised the study. We thank our collaborators who helped set up the COVID-PCD study: Cristina Ardura, Yin Ting Lam, Christina Mallet, Helena Koppe, Dominique Rubi from the University of Bern and Jane S Lucas and Amanda Harris from the University Hospital Southampton. We thank Nathalie Massin and Lara Gonçalves Pissini for their help in the design of the fertility questionnaire. We thank Kristin Marie Bivens for her editorial work and guidance on our manuscript.
Declarations
Ethics approval and consent to participate
Bern Cantonal Ethics Committee (Kantonale Ethikkomission Bern) approved our study (Study ID: 2020-00830). Participants provide their informed consent to participate in the study at registration. Participation is anonymous. Participants can withdraw consent to participate at any time by contacting the study team.
Funding
Our research was funded by the Swiss National Science Foundation, Switzerland (SNSF 320030B_192804/1), the Swiss Lung Association, Switzerland (2021- 08_Pedersen), and we also received support from the PCD Foundation, United States; the Verein Kartagener Syndrom und Primäre Ciliäre Dyskinesie, Germany; the PCD Support UK; and PCD Australia, Australia. M. Goutaki receives funding from the Swiss National Science Foundation (PZ00P3_185923). Study authors participate in the BEAT-PCD Clinical Research Collaboration supported by the European Respiratory Society.
Competing interests
All authors declare no conflict of interest.
Availability of data and materials
COVID-PCD data is available upon reasonable request by contacting Claudia Kuehni (claudia.kuehni@unibe.ch).